Several naturally-occurring alkaloids obtainable from Vinca rosea have been found active in the treatment of experimental malignancies in animals. Among these are leurosine (U.S. Pat. No. 3,370,057), vincaleukoblastine (vinblastine) to be referred to hereinafter as VLB (U.S. Pat. No. 3,097,137), leurosidine (vinrosidine) and leurocristine (VCR or vincristine) (both in U.S. Pat. No. 3,205,220), deoxy VLB "A" and "B", Tetrahedron Letters, 783 (1968) (desacetyl leurosine hydrazide is also disclosed therein); 4-desacetoxy vinblastine (U.S. Pat. No. 3,954,773); 4-desacetoxy-3'-hydroxyvinblastine (U.S. Pat. No. 3,944,554); leurocolombine (U.S. Pat. No. 3,890,325), leuroformine (N-formylleurosine, see Belgian Pat. No. 811,110) and vincadioline (U.S. Pat. No. 3,887,565). Two of these alkaloids, VLB and leurocristine, are now marketed as drugs for the treatment of malignancies in humans, particularly the leukemias and related diseases.
The dimeric indole-dihydroindole alkaloids obtainable from Vinca rosea can be represented by the formula: ##STR1##
In the above formula where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, VLB is represented; where R.sup.1 is acetoxy, R.sup.2 is formyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, vincristine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl, R.sup.4 is hydroxyl, and R.sup.5 is H, leurosidine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 and R.sup.5 are H and R.sup.4 is ethyl, deoxy VLB "A" is represented; where R.sup.1, R.sup.2 and R.sup.5 are the same as in deoxy VLB "A" but R.sup.3 is ethyl and R.sup.4 is hydrogen, deoxy VLB "B" is represented; and where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl and R.sup.4 and R.sup.5 taken together form an .alpha.-epoxide ring, leurosine is represented.
Of the above alkaloids, vincristine is the most useful, and the least available, from vinca. Recently, Jovanovics et al., U.S. Pat. No. 3,899,493, have developed an oxidative method for converting the relatively more abundant VLB into vincristine by chromic acid oxidation at low (-60.degree. C.) temperatures. There are other relatively abundant alkaloids such as leurosine in the dimeric indole-dihydroindole fraction from vinca and it would be desirable to convert these directly or indirectly to vincristine or to a drug of comparable oncolytic activity. It is known that leurosine can be converted to deoxy VLB "B" (along with varying amounts of deoxy VLB "A") by treatment with Raney nickel in refluxing absolute ethanol--see Neuss, Gorman, Cone and Huckstep, Tetrahedron Letters 783-7 (1968). While leurosine demonstrated oncolytic activity in experimental tumors in mice, clinical response was limited. Deoxy VLB "A" and deoxy VLB "B" were reported to lack reproducible activity in experimental tumors in mice.
It is an object of this invention to convert leurosine via deoxy VLB "A" and "B" to oncolytically-active derivatives of deoxy VLB "A" and "B", thereby converting indirectly the relatively abundant alkaloid leurosine into a drug of greater potential clinical utility.